Treatment of congestive heart failure with growth hormone secretagogues

Abstract

The present invention is directed to methods for the modulation of cardiac function which comprise the administration of certain compounds, as defined herein, having growth hormone secretagogue activity.

We claim:  
     
       1. A method of modulating cardiac function which comprises administering to a patient in need thereof an effective amount of GRP-2. 
     
     
       2. A method of modulating cardiac function which comprises administering to a patient in need thereof an effective amount of a compound of formula I                    
       wherein: 
       A is C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylaryl, C 1 -C 6 alkyl(O)C 1 -C 6 alkylaryl, C 1 -C 6 alkyl(S)C 1   14  C 6 alkylaryl, indolyl, indolinyl, thienyl, (C 1 -C 6 alkyl)thienyl, benzothienyl, benzofuranyl, naphthanyl, cyclohexyl, (C 1 -C 6 alkyl)indolyl, (C 1 -C 6 alkyl)benzothienyl, (C 1 -C 6 alkyl)naphthanyl, (C 1 -C 6 alkyl)benzofuranyl, and (C 1 -C 6 alkyl)cyclohexyl;  
       B is NH 2 , NHR 1 , C 1 -C 6 alkylNH 2 , C 1 -C 6 alkylNHR 1 , C 1 -C 6 alkylarylNH 2 , C 1 -C 6 alkylarylNHR 1 , C 1 -C 6 alkylcyclohexylNH 2 , C 1 -C 6 alkylcyclohexylNHR 1 , R 1 -piperidin-3-yl(C 1 -C 6 alkyl), R 1 -piperidin-2-yl(C 1 -C 6 alkyl), R 1 -piperidin-4-yl(C 1 -C 6 alkyl), R 1 -quinolin-2-yl(C 1 -C 6 alkyl), R 1 -(2,4-dihydroquinolin-2-yl(C 1 -C 6 alkyl), R 1 -isoquinolin-2-yl(C 1 -C 6 alkyl), and R 1 -(2,4-dihydroisoquinolin-2-yl(C 1 -C 6 alkyl);  
       R 1  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl(OH), or C 1 -C 6 alkylenyl(OH)R 2 ;  
       R 2  is C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkyl(O)C 1 -C 6  alkyl, C(O)O—C 1 -C 6  alkyl, aryl, or C 1 -C 6 alkylaryl;  
       X is C 1 -C 6 alkylenyl, O, S, NH, or N(C 1 -C 6 alkyl);  
       V is selected from the group consisting of                    
       W is S, O, NH, or CH 2 ;  
       Y is N or CH;  
       Z is N or CH;  
       Y′ is N or CH;  
       Z′ is N or CH;  
       R 4  and R 5  are independently hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylaryl, C(O)O(C 1 -C 6 alkyl), C(O)N(C 1 -C 6 alkyl) 2 , or C 1 -C 6 alkylCOR 7 ;  
       R 7  is hydrogen, C 1 -C 6 alkyl, pyrrolidinyl, piperidinyl, homoproline, or proline;  
       D is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl(O)(CO)C 1 -C 6 alkyl, C 1 -C 6 alkyl(O)(CO)N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkylaryl, C(O)R 6 , C 1 -C 6 alkyl(O)R 6 , C 1 -C 6 alkyl(OH), C 1 -C 6 alkylC(O)R 6 , C 1 -C 6 alkylR 6 aryl, (C 1 -C 6 alkyl)NHSO 2 (C 1 -C 6 alkyl), (C 1 -C 6 alkyl)NHSO 2 (aryl);  
       R 6  is H, C 1 -C 6 alkyl, aryl, naphthyl, C 1 -C 6 alkylaryl, acetyl, NH 2 , NH(C 1 -C 6 alkyl), NH(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), NH(C 1 -C 6 alkyl)S(C 1 -C 6 alkyl), NH(C 1 -C 6 alkylidenyl)OCH 3 , NH(C 1 -C 6 alkyl)aryl, NH(C 3 -C 6  cycloalkyl), NH(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), NH(C 1 -C 6 alkyl)NH(C 1 -C 6 alkyl), NH(C 1 -C 6 alkyl)NH(C 1 -C 6 alkylaryl), NHSO 2 (C 1 -C 6 alkylaryl), NH(C 1 -C 6 alkyl)C(O)O(C 1 -C 6 alkyl), NH(naphthyl), N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)(aryl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkylaryl), O(C 1 -C 6 alkyl), O(aryl), O(C 1 -C 6 alkylaryl), piperidinyl, piperidinyl-C(O)NH(C 1 -C 6 alkyl), piperidinyl-C(O)NH(C 1 -C 6 alkylaryl), piperidinyl-C(O)N(C 1 -C 6 alkyl) 2 , piperidinyl-C(O)N(C 1 -C 6 alkyl)(aryl), pyrrolidinyl, pyrrolidinyl C(O)NH(aryl), pyrrolidinyl C(O)NH(C 1 -C 6 alkyl), pyrrolidinyl C(O)N(C 1 -C 6 alkyl) 2 , pyrrolidinyl C(O)NH(C 1 -C 6 alkylaryl), pyrrolidinyl C(O)NH(C 1 -C 6 alkyl)(aryl), pyrrolinyl, morpholino, hexamethyleneimino, heptamethyleneimino, quinolinyl, 2,4-dihydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, indolinyl, an amino acid selected from the group consisting of proline, homoproline, glycine, alanine, valine, leucine, isoleucine, tyrosine, tryptophan, phenylalanine, serine, threonine, asparagine, glutamic acid, aspartic acid, lysine, arginine, glutamine, histidine, cysteine, and methionine, or a nitrogen-containing heterocycle selected from the group consisting of                    
       E is hydrogen, C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl, aryl, (aryl)C(O)NR 6 , (aryl)(C 1 -C 6 alkyl)C(O)R 6 , C 1 -C 6 alkylaryl, C(O)aryl, C 1 -C 6  alkylC(O)aryl, naphthyl, C 1 -C 6 alkylnaphthyl, C(O)naphthyl, C 1 -C 6 alkylC(O)naphthyl, heteroaryl, C 1 -C 6 alkylheteroaryl, C(O)heteroaryl, C 1 -C 6  alkylC(O)heteroaryl, indanyl, C 1 -C 6 alkylindanyl, C(O)indanyl, C 1 -C 6 alkylC(O)indanyl, cycloalkyl;  
       or D and E combine to form indanyl, fluorenyl, or cycloalkyl;  
       G is hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylaryl, and C 1 -C 6 alkenyl;  
       J is hydrogen, C 1 -C 6 alkyl, aryl, and C 1 -C 6 alkylaryl;  
       L is hydrogen, C 1 -C 6 alkyl, C(O)OC 1 -C 6 alkyl, aryl, C 1 -C 6 alkylaryl, C(O)OC 1 -C 6 alkylaryl, C 1 -C 6 alkenyl, —F, and —CN, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, C 1 -C 6 alkyl-C(O)R 6 ;  
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
       3. A method according to claim  2  wherein A is selected from the group consisting of                    
     
     
       4. A method according to claim  2  wherein B is                    
     
     
       5. A method according to claim  3  wherein X is NH. 
     
     
       6. A method according to claim  2  wherein V is selected from the group consisting of                    
     
     
       7. A method according to claim  2  wherein D is —C(O)R 6 , and R 6  is 1-pyrrolidinyl, 1-piperidinyl, 4-methoxy-1-piperidinyl,                    
     
     
       8. A method according to claim  2  wherein E is                    
     
     
       9. A method according to claim  2  wherein said patient is a human. 
     
     
       10. A method for the treatment or prevention of congestive heart failure which comprises administering to a patient in need of said treatment an effective amount of GRP-2, wherein the GRP-2 increases the levels of endogenous growth hormone. 
     
     
       11. A method for the treatment or prevention of congestive heart failure which comprises administering to a patient in need of said treatment an effective amount of a compound of formula I                    
       wherein: 
       A is C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylaryl, C 1 -C 6 alkyl(O)C 1 -C 6 alkylaryl, C 1 -C 6 alkyl(S)C 1 -C 6 alkylaryl, indolyl, indolinyl, thienyl, (C 1 -C 6 alkyl)thienyl, benzothienyl, benzofuranyl, naphthanyl, cyclohexyl, (C 1 -C 6 alkyl)indolyl, (C 1 -C 6 alkyl)benzothienyl, (C 1 -C 6 alkyl)naphthanyl, (C 1 -C 6 alkyl)benzofuranyl, and (C 1 -C 6 alkyl)cyclohexyl;  
       B is NH 2 , NHR 1 , C 1 -C 6 alkylNH 2 , C 1 -C 6 alkylNHR 1 , C 1 -C 6 alkylaryl NH 2 , C 1 -C 6 alkylarylNHR 1 , C 1 -C 6 alkylcyclohexylNH 2 , C 1 -C 6 alkylcyclohexylNHR 1 , R 1 -piperidin-3-yl(C 1 -C 6 alkyl), R 1 -piperidin-2-yl(C 1 -C 6 alkyl), R 1 -piperidin-4-yl(C 1 -C 6 alkyl), R 1 -quinolin-2-yl(C 1 -C 6 alkyl), R 1 -(2,4-dihydroquinolin-2-yl(C 1 -C 6 alkyl), R 1 -isoquinolin-2-yl(C 1 -C 6 alkyl), and R 1 -(2,4-dihydroisoquinolin-2-yl(C 1 -C 6 alkyl);  
       R 1  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl(OH), or C 1 -C 6 alkylidenyl(OH)R 2 ;  
       R 2  is C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkyl(O)C 1 -C 6  alkyl, C(O)O—C 1 -C 6  alkyl, aryl, or C 1 -C 6 alkylaryl;  
       X is C 1 -C 6 alkylenyl, O, S, NH, or N(C 1 -C 6 alkyl);  
       V is selected from the group consisting of                    
       W is S, O, NH, or CH 2 ;  
       Y is N or CH;  
       Z is N or CH;  
       Y′ is N or CH;  
       Z′ is N or CH;  
       R 4  and R 5  are independently hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylaryl, C(O)O(C 1 -C 6 alkyl), C(O)N(C 1 -C 6 alkyl) 2 , or C 1 -C 6 alkylCOR 7 ;  
       R 7  is hydrogen, C 1 -C 6 alkyl, pyrrolidinyl, piperidinyl, homoproline, or proline;  
       D is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl(O)(CO)C 1 -C 6 alkyl, C 1 -C 6 alkyl(O)(CO)N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkylaryl, C(O)R 6 , C 1 -C 6 alkyl(O)R 6 , C 1 -C 6 alkyl(OH), C 1 -C 6 alkylC(O)R 6 , C 1 -C 6 alkylR 6 , aryl, (C 1 -C 6 alkyl)NHSO 2 (C 1 -C 6 alkyl), (C 1 -C 6 alkyl)NHSO 2 (aryl);  
       R 6  is H, C 1 -C 6 alkyl, aryl, naphthyl, C 1 -C 6 alkylaryl, acetyl, NH 2 , NH(C 1 -C 6 alkyl), NH(C 1 -C 6 alkyl)O(C 1 -C 6 alkyl), NH(C 1 -C 6 alkyl)S(C 1 -C 6 alkyl), NH(C 1 -C 6 alkylidenyl)OCH 3 , NH(C 1 -C 6 alkyl)aryl, NH(C 3 -C 6  cycloalkyl), NH(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), NH(C 1 -C 6 alkyl)NH(C 1 -C 6 alkyl), NH(C 1 -C 6 alkyl)NH(C 1 -C 6 alkylaryl), NHSO 2  (C 1 -C 6 alkylaryl), NH(C 1 -C 6 alkyl)C(O)O(C 1 -C 6 alkyl), NH(naphthyl), N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)(aryl), N(C 1 -C 6 alkyl)(C 1 -C 6 alkylaryl), O(C 1 -C 6 alkyl), O(aryl), O(C 1 -C 6 alkylaryl), piperidinyl, piperidinyl-C(O)NH(C 1 -C 6 alkyl), piperidinyl-C(O)NH(C 1 -C 6 alkylaryl), piperidinyl-C(O)N(C 1 -C 6 alkyl) 2 , piperidinyl-C(O)N(C 1 -C 6 alkyl)(aryl), pyrrolidinyl, pyrrolidinyl C(O)NH(aryl), pyrrolidinyl C(O)NH(C 1 -C 6 alkyl), pyrrolidinyl C(O)N(C 1 -C 6 alkyl) 2 , pyrrolidinyl C(O)NH(C 1 -C 6 alkylaryl), pyrrolidinyl C(O)NH(C 1 -C 6 alkyl)(aryl), pyrrolinyl, morpholino, hexamethyleneimino, heptamethyleneimino, quinolinyl, 2,4-dihydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, indolinyl, an amino acid selected from the group consisting of proline, homoproline, glycine, alanine, valine, leucine, isoleucine, tyrosine, tryptophan, phenylalanine, serine, threonine, asparagine, glutamic acid, aspartic acid, lysine, arginine, glutamine, histidine, cysteine, and methionine, or a nitrogen-containing heterocycle selected from the group consisting of                    
       E is hydrogen, C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl, aryl, (aryl)C(O)NR 6 , (aryl)(C 1 -C 6 alkyl)C(O)R 6 , C 1 -C 6 alkylaryl, C(O)aryl, C 1 -C 6 alkylC(O)aryl, naphthyl, C 1 -C 6 alkylnaphthyl, C(O)naphthyl, C 1 -C 6 alkylC(O)naphthyl, heteroaryl, C 1 -C 6 alkylheteroaryl, C(O)heteroaryl, C 1 -C 6 alkylC(O)heteroaryl, indanyl, C 1 -C 6 alkylindanyl, C(O)indanyl, C 1 -C 6 alkylC(O)indanyl, cycloalkyl;  
       or D and E combine to form indanyl, fluorenyl, or cycloalkyl;  
       G is hydrogen, C 1 -C 6 alkyl, aryl, C 1 -C 6 alkylaryl, and C 1 -C 6 alkenyl;  
       J is hydrogen, C 1 -C 6 alkyl, aryl, and C 1 -C 6 alkylaryl;  
       L is hydrogen, C 1 -C 6 alkyl, C(O)OC 1 -C 6 alkyl, aryl, C 1 -C 6 alkylaryl, C(O)OC 1 -C 6 alkylaryl, C 1 -C 6 alkenyl, —F, and —CN, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, C 1 -C 6 alkyl-C(O)R 6 ;  
       or a pharmaceutically acceptable salt or solvate thereof; 
       wherein the compound of formula I increases the levels of endogenous growth hormone.  
     
     
       12. A method according to claim  11  wherein said patient is a human. 
     
     
       13. A method according to claim  2  which further comprises the administration of an effective amount of an angiotensin converting enzyme (ACE) inhibitor. 
     
     
       14. A method according to claim  2  which further comprises the administration of an effective amount of an antihypertensive agent. 
     
     
       15. A method according to claim  2  which further comprises the administration of an effective amount of a diuretic. 
     
     
       16. A method according to claim  2  which further comprises the administration of an effective amount of a β-blocker. 
     
     
       17. A method according to claim  11  which further comprises the administration of an effective amount of an angiotensin converting enzyme (ACE) inhibitor. 
     
     
       18. A method according to claim  11  which further comprises the administration of an effective amount of an antihypertensive agent. 
     
     
       19. A method according to claim  11  which further comprises the administration of an effective amount of a diuretic. 
     
     
       20. A method according to claim  11  which further comprises the administration of an effective amount of a β-blocker. 
     
     
       21. A method of diminishing loss of body weight in a mammal following congestive heart failure which comprises the administration of a therapeutically effective amount of GRP-2. 
     
     
       22. A method of enhancing recovery of a mammal following congestive heart failure which comprises the administration of a therapeutically effective amount of GRP-2. 
     
     
       23. A method for screening compounds having growth hormone secretagogue activity for the ability to modulate cardiac function, which comprises the administration of said compounds to a SHHF/Mcc-fa   cp    rat, wherein said rat exhibits congestive heart failure. 
     
     
       24. A method according to claim  1  wherein said patient is a human. 
     
     
       25. A method according to claim  1  which further comprises the administration of an effective amount of an angiotensin converting enzyme (ACE) inhibitor. 
     
     
       26. A method according to claim  1  which further comprises the administration of an effective amount of an antihypertensive agent. 
     
     
       27. A method according to claim  1  which further comprises the administration of an effective amount of a diuretic. 
     
     
       28. A method according to claim  1  which further comprises the administration of an effective amount of a β-blocker. 
     
     
       29. A method according to claim  10  which further comprises the administration of an effective amount of an angiotensin converting enzyme (ACE) inhibitor. 
     
     
       30. A method according to claim  10  which further comprises the administration of an effective amount of an antihypertensive agent. 
     
     
       31. A method according to claim  10  which further comprises the administration of an effective amount of a diuretic. 
     
     
       32. A method according to claim  10  which further comprises the administration of an effective amount of a β-blocker. 
     
     
       33. A method according to claim  10  wherein said patient is a human.